Microproteins shed new light on medulloblastoma
New research confirms the crucial role of certain microproteins in the development of medulloblastoma. Researchers from the Princess Máxima Center and Michigan Medicine were able to determine this with new, refined techniques. The findings contribute to possible new, targeted treatments that tackle this aggressive form of brain cancer at a molecular level.
Every year, around 180 children in the Netherlands are diagnosed with a brain tumor. Some 20 children are diagnosed with medulloblastoma, a fast-growing tumor in the hindbrain. The chance of a cure varies: it depends on the subtype and whether the disease has spread. One in four children with medulloblastoma suffers from long-term memory loss and speech problems after surgery. New treatments with fewer side effects are sorely needed.
Microproteins
Microproteins are made from parts of DNA that were not previously known to be able to make protein. The Van Heesch group investigates the role these small proteins play in the origin, development and treatment of childhood cancer. Microproteins remained hidden for a long time, partly because they were too small to be properly mapped. In new research, published today in the journal Molecular Cell, researchers shed new light on the role of microproteins in medulloblastoma.
Damon Hofman, PhD student in the Van Heesch group and co-first author: ‘For the first time, we have mapped and studied microproteins 4that are essential in medulloblastoma. This was possible thanks to new, more refined techniques. We were now able to demonstrate which micro-proteins and mechanisms are essential for the survival of a cancer cell.’
Dr. John Prensner, M.D., assistant professor of Pediatrics and Biological Chemistry at Michigan Medicine, and one of the study's lead authors, says: ‘This research is critical in helping us begin to understand how medulloblastoma works on a genetic and cellular level so that patients can be treated, and new therapies can be developed, accordingly.’
Upstream open reading frames
To determine which microproteins are essential for medulloblastoma, the researchers studied so-called 'upstream open reading frames'. Hofman explains: ‘Microproteins and normal proteins are made from exactly the same piece of genetic material, but come from different parts of that molecule. One of the sections that plays a role in the production of micro-proteins is called ‘upstream ORFs’. Until now, these uORFs have been relatively underexposed, especially in childhood cancers and specifically in medulloblastoma.’
To find out which protein – normal, micro or both – the cancer cell needs most, the researchers cut the upstream ORF part from the cell using CRISPR gene editing technology. They saw a clear effect. Without the microproteins, the medulloblastoma cancer cells could not survive. The known proteins could be disabled without having an effect on the cancer cell.
Very specifically, the microprotein ASNSD1-uORF could be designated as essential in children with a so-called MYC mutation in the DNA. This is a high-risk group of medulloblastoma with the lowest chance of survival.
Other forms of childhood cancer
Dr. Sebastiaan van Heesch, research group leader and junior Oncode researcher, calls the results promising: ‘The results from this study show the potential of this still young research field. They confirm the crucial role of certain essential microproteins in the origin and development of medulloblastoma. Further research is now needed to determine how these microproteins can be used as targets for cancer-specific immunotherapy and to reveal their full therapeutic potential. This is a major motivation for us for further research in which we will also map out the essential micro-proteins for other forms of childhood cancer.’
Source: Prinses Máxima Center
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